Elucidating Shared Genetic Associations Between Birth Weight and Cardiovascular Diseases

Background/Objectives: Birth weight (BW) is an established early-life indicator associated with later-life cardiovascular diseases (CVDs). However, it remains unclear whether this lifelong association shares a common genetic foundation. Methods: Using unadjusted summary statistics from genome-wide association studies (GWAS) of continuous BW and seven CVDs, we employed a suite of genetic approaches to assess genetic correlations, identify pleiotropic loci, and perform gene-based and functional enrichment analyses. To prioritize candidate genes, we integrated transcriptomic data from umbilical cord blood and DNA methylation quantitative trait locus (mQTL) analyses. Results: We observed significant negative genetic correlations between BW and five CVDs using LDSC (and six CVDs using HDL), while GPA demonstrated significant genetic overlap across all seven CVDs. Our analysis identified 10,169 pleiotropic single-nucleotide polymorphisms, which mapped to 362 distinct loci and 85 colocalized signals. Gene-based analysis revealed 815 candidate pleiotropic genes, which were significantly enriched in metabolic pathways and organ development processes. Cell- and tissue-specific enrichment highlighted the relevance of arteries (aorta and coronary artery), skeletal muscle, esophagus, and adrenal gland, alongside kidney-derived cells. Finally, by integrating differential gene expression and mQTL data, we prioritized key candidate genes (including GPSM1, EHBP1L1, and CLDN7) for future functional investigation. Conclusions: Our study characterizes the shared genetic landscape between birth weight and cardiovascular health, providing insights into the shared genetic architecture linking early developmental liability to adult disease risk. The prioritized loci and candidate genes offer a valuable foundation for future mechanistic and functional research.